Abstract: Development of immunization strategies to reshape pathogenic microbiomes to a healthy state Project summary The normal gut microbiota are implicated in an increasing number of chronic inflammatory diseases that are prevalent in our modern society, such as obesity and metabolic syndrome. The diseases linked to the composition of the microbiota of the gut in particular will benefit from common therapeutic approaches, although none are currently available. 'Reshaping'the microbiota to a healthy state using immunization aimed at stimulating the production of anti- bacterial secretory immunoglobin (IgA) is a novel approach that could be widely applied. The disease model I will use in this proposed research is a recently described mouse model for metabolic syndrome in which the gut microbes are directly implicated. To determine how IgA shapes the normal and disease- causing gut microbiota, metagenomic analyses will characterize and track temporal shifts of phylogenetic and functional diversity of IgA-coated and uncoated microbial cells in the gut, as well as those bacterial cells sampled by dendritic cells. To reshape the microbiota to a healthy state, we will immunize mice against targeted bacterial species and/or consortia, tracking the response of the microbiota over time. The impact of immunizations on gut microbial phylogenetic diversity and functional gene content will be monitored with high- throughput sequence-based analyses. This proposed research is highly innovative as it integrates microbial ecology, metagenomics and immunology to find a solution to the newly emergent and unstudied problem of how to redress pathogenic lineage imbalances in the microbiota. The approach is risky because the role of the adaptive immune system in shaping communities is not well understood. However, the pay-off has the potential to be very high: this research could translate rapidly into therapies for use in children and adults at risk for metabolic syndrome or other diseases related to pathogenic alterations in community composition. Public Health Relevance: This research seeks a therapeutic strategy for a range of prevalent, chronic inflammatory diseases that have recently been attributed to an imbalance in the normal microbes associated with the human body. Those suffering from obesity-related diseases may be the biggest beneficiaries: rates of obesity are dangerously high, and amongst children in particular, obesity rates are increasing, leading to the possibility that this is the first generation that will die before their parents from obesity-related diseases such as metabolic syndrome. The techniques developed through this research could be applied to any disease found to be related to an imbalanced normal microbiota.